Project Summary Diisopropylfluorophosphate (DFP) is an organophosphate (OP) cholinesterase inhibitor that is listed as a chemical threat agent by the U.S. Department of Homeland Security. Human and animal survivors of acute OP exposure exhibit structural brain damage and long-term impairments in learning and memory. Current research efforts to develop more effective therapeutic strategies for treating patients acutely intoxicated with DFP is largely focused on the adult brain and fails to address subpopulations that may be at greater risk, such as children. The goal of this research project is to evaluate mechanisms of DFP-induced neurological damage in the juvenile brain to inform therapeutic targets with the long-term goal of developing medical countermeasures that will protect children in the event of a chemical emergency involving acute OP exposures. The central hypothesis of this proposal is that acute DFP intoxication of the juvenile brain results in persistent neurological damage that is mediated by microglial activation. To test this hypothesis, the following specific aims will be addressed: (1) characterize the neurological sequelae in juvenile rats acutely intoxicated with DFP; and (2) test the hypothesis that microglial activation mediates the adverse effects of acute DFP intoxication on cognitive behavior and/or neurodegeneration. Aim 1 will be accomplished by addressing the following sub-aims: (1a) establish the dose-response relationship of DFP-induced seizure behavior in postnatal day (P) 28 juvenile rats; and (1b) determine whether acute DFP intoxication of the juvenile brain results in persistent cognitive deficits and/or neurodegeneration. Aim 2 will be accomplished by addressing the following sub-aims: (2a) establish the spatiotemporal profile of neuroinflammation following acute DFP intoxication of P28 rats; and (2b) determine whether pharmacological attenuation of microglial activation mitigates DFP- induced neuropathology and/or cognitive deficits. The proposed research will be conducted at the University of California, Davis, a leading biomedical research institution that houses a variety of centers with expertise in areas relevant to the proposed research, including medical countermeasures against chemical threat agents, cutting-edge in vivo imaging modalities, rat behavioral assays as they apply to neurodevelopment, and biostatistics. This environment, in combination with the expertise of the mentor, will provide the foundation for the PI's training in developmental neurotoxicology and neuropharmacology, advanced imaging techniques and neurobehavioral studies, quantitative science and data analysis, teaching and mentoring, and professional development. Together, this training will be a critical first step in the development of the PI as an independent researcher in developmental neurotoxicology.